Blood–brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses

Pardridge, William M.

doi:10.1016/j.jconrel.2007.04.001

Cited by 80 publications

(51 citation statements)

References 36 publications

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“…Research endeavour that followed these pioneer works ascribed this observation to the BBB. Located at the blood/ brain interface, this barrier represents the primary obstacle to CNS penetration for blood circulating therapeutics (5).…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy

Bellavance

Blanchette

Fortin

2008

AAPS J

165

113

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Abstract. The blood-brain barrier (BBB) is a complex functional barrier composed of endothelial cells, pericytes, astrocytic endfeets and neuronal cells. This highly organized complex express a selective permeability for molecules that bear, amongst other parameters, adequate molecular weight and sufficient liposolubility. Unfortunately, very few therapeutic agents currently available do cross the BBB and enters the CNS. As the BBB limitation is more and more acknowledged, many innovative surgical and pharmacological strategies have been developed to circumvent it. This review focuses particularly on the osmotic opening of the BBB, a well-documented approach intended to breach the BBB. Since its inception by Rapoport in 1972, pre-clinical studies have provided important information on the extent of BBB permeation. Thanks to Neuwelt and colleagues, the osmotic opening of the BBB made its way to the clinic. However, many questions remain as to the detailed physiology of the procedure, and its best application to the clinic. Using different tools, amongst which MRI as a real-time in vivo characterization of the BBB permeability and CNS delivery, we attempt to better define the osmotic BBB permeabilization physiology. These ongoing studies are described, and data related to spatial and temporal distribution of a molecule after osmotic BBB breaching, as well as the window of BBB permeabilization, are discussed. We also summarize recent clinical series highlighting promising results in the application of this procedure to maximize delivery of chemotherapy in the treatment of brain tumor patients.KEY WORDS: blood-brain barrier, blood-brain barrier disruption, brain tumors, CNS delivery; MRI.

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Section: Introductionmentioning

confidence: 99%

Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy

Bellavance

Blanchette

Fortin

2008

AAPS J

165

113

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show abstract

“…For this purpose, the amino acid building block Fmoc−Lys(tris-tBu-DOTA)−OH (23) was synthesized and implemented into routine Fmoc-SPPS, giving improved yields compared to standard peptide scaffold synthesis, subsequent side-chain deprotection, and chelator functionalization. AngioPep-2 was further reacted on a solid support with PEG linkers of different lengths (PEG 3 , PEG 5 , PEG 7 , and PEG 11 ) and maleimidohexanoic acid. After cleavage from the resin and purification, the peptide derivatives were conjugated to FP-T (1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Shuttle–Cargo Fusion Molecules of Transport Peptides and the hD_2/3Receptor Antagonist Fallypride: A Feasible Approach To Preserve Ligand–Receptor Binding?

et al. 2014

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Access and use of this website and the material on it are subject to the Terms and Conditions set forth at Vous avez des questions? Nous pouvons vous aider. Pour communiquer directement avec un auteur, consultez la première page de la revue dans laquelle son article a été publié afin de trouver ses coordonnées. Si vous n'arrivez pas à les repérer, communiquez avec nous à PublicationsArchive-ArchivesPublications@nrc-cnrc.gc.ca. Questions? Contact the NRC Publications Archive team atPublicationsArchive-ArchivesPublications@nrc-cnrc.gc.ca. If you wish to email the authors directly, please see the first page of the publication for their contact information. NRC Publications Archive Archives des publications du CNRCThis publication could be one of several versions: author's original, accepted manuscript or the publisher's version. / La version de cette publication peut être l'une des suivantes : la version prépublication de l'auteur, la version acceptée du manuscrit ou la version de l'éditeur. For the publisher's version, please access the DOI link below./ Pour consulter la version de l'éditeur, utilisez le lien DOI ci-dessous.http://doi.org/10.1021/jm5004123Journal of Medicinal Chemistry, 57, 10, pp. 4368-4381, 2014-04-30 Shuttle ABSTRACT: To determine if the conjugation of a small receptor ligand to a peptidic carrier to potentially facilitate transport across the blood−brain barrier (BBB) by "molecular Trojan horse" transcytosis is feasible, we synthesized several transport peptide−fallypride fusion molecules as model systems and determined their binding affinities to the hD 2 receptor. Although they were affected by conjugation, the binding affinities were found to be still in the nanomolar range (between 1.5 and 64.2 nM). In addition, homology modeling of the receptor and docking studies for the most potent compounds were performed, elucidating the binding modes of the fusion molecules and the structure elements contributing to the observed high receptor binding. Furthermore, no interaction between the hybrid compounds and P-gp, the main excretory transporter of the BBB, was found. From these results, it can be inferred that the approach to deliver small neuroreceptor ligands across the BBB by transport peptide carriers is feasible.

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“…In vivo, PEG-coated liposomes have been modified with monoclonal antibodies in order to reach the CNS. A liposome is coated with peptidomimetic monoclonal antibodies that undergo receptor-mediated transcytosis across the blood-brain barrier on the endogenous peptide receptor transporters (Pardridge, 2007). These Trojan horses (figure 3) may use the insulin or transferrin receptor, and since the MAb binding site is different from the binding site of the endogenous ligand, there is no interference of endogenous ligand transport (Skarlatos et al, 1995).…”

Section: Liposomes and Nanotechnologymentioning

confidence: 99%

Non Viral Gene Transfer Approaches for Lysosomal Storage Disorders

Matte¹,

Baldo²,

Giugliani³

2011

Non-Viral Gene Therapy

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Blood–brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses

Cited by 80 publications

References 36 publications

Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy

Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy

Shuttle–Cargo Fusion Molecules of Transport Peptides and the hD_2/3Receptor Antagonist Fallypride: A Feasible Approach To Preserve Ligand–Receptor Binding?

Non Viral Gene Transfer Approaches for Lysosomal Storage Disorders

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Blood–brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses

Cited by 80 publications

References 36 publications

Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy

Recent Advances in Blood–Brain Barrier Disruption as a CNS Delivery Strategy

Shuttle–Cargo Fusion Molecules of Transport Peptides and the hD2/3Receptor Antagonist Fallypride: A Feasible Approach To Preserve Ligand–Receptor Binding?

Non Viral Gene Transfer Approaches for Lysosomal Storage Disorders

Contact Info

Product

Resources

About

Shuttle–Cargo Fusion Molecules of Transport Peptides and the hD_2/3Receptor Antagonist Fallypride: A Feasible Approach To Preserve Ligand–Receptor Binding?